Fibrinogen receptor antagonists

ABSTRACT

PCT No. PCT/US93/09730 Sec. 371 Date May 31, 1995 Sec. 102(e) Date May 31, 1995 PCT Filed Oct. 12, 1993 PCT Pub. No. WO94/08962 PCT Pub. Date Apr. 28, 1994Fibrinogen receptor antagonists of the formula:   &lt;IMAGE&gt;   wherein A,B,D,E,Y are as defined in the specification, are disclosed for use in inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets.

This application is a 371 of PCT/US 93/09730 filed Oct. 13, 1993 whichis a CIP of U.S. application Ser. No. 07/960,668 filed Oct. 14, 1992,now abandoned.

FIELD OF THE INVENTION

This invention relates to the discovery of fibrinogen receptorantagonists of Formula I for use in inhibiting the binding of fibrinogento blood platelets and inhibiting the aggregation of blood plateletswhen administered to mammals, preferably humans.

BACKGROUND OF THE INVENTION

The interaction of platelets with the coagulation and fibrinolyticsystems in the maintenance of hemostasis may become pathogenic,requiring prevention and treatment. The fibrinogen receptor antagonistsof Formula I are useful in treating various diseases related to plateletaggregation and fibrin formation.

An interest in platelet inhibitors has reemerged as a result of a betterunderstanding of the role of platelets and thrombosis in thepathogenesis of vascular disease, including unstable angina, acutemyocardial infarction and stroke.

Platelets are cell-like anucleated fragments, found in the blood of allmammals which participate in blood coagulation. Fibrinogen is aglycoprotein present as a normal component of blood plasma. Fibrinogenparticipates in platelet aggregation and fibrin formation in the bloodclotting mechanism. Platelets are deposited at sites of vascular injurywhere multiple physiological agonists act to initiate plateletaggregation culminating in the formation of a platelet plug to minimizeblood loss. If the platelet plug occurs in the lumen of a blood vessel,normal blood flow is impaired.

Platelet membrane receptors are essential in the process of plateletadhesion and aggregation. Interaction of fibrinogen with a receptor onthe platelet membrane complex IIb/IIIa is known to be essential fornormal platelet function.

Zimmerman et al., U.S. Pat. No. 4,683,291, describes peptides havingutility in the study of fibrinogen-platelet, platelet-platelet, andcell-cell interactions. The peptides are described as having utilitywhere it is desirable to retard or prevent formation of a thrombus orclot in the blood.

Pierschbacher et al., U.S. Pat. No. 4,589,881, describes the sequence ofan 11.5 kDal polypeptide fragment of fibronectin which embodies thecell-attachment-promoting activity of fibronectin.

Ruoslahti et al., U.S. Pat. No. 4,614,517, describes tetrapeptides whichalter cell-attachment activity of cells to various substrates. Ruoslahtiet al., U.S. Pat. No. 4,578,079, describes similar tetrapeptides havingSer substituted with Thr or Cys.

Pierschbacher et al., Proc. Natl. Acad. Sci. USA, Vol. 81, pp.5985-5988, October, 1984, describe variants of the cell recognition siteof fibronectin that retain attachment-promoting activity. Pierschbacheret. al. further assayed the cell attachment-promoting activities of anumber of structures closely resembling the Arg-Gly-Asp-Ser peptide, andfound "that the arginine, glycine, and aspartate residues cannot bereplaced even with closely related amino acids, but that several aminoacids can replace serine without loss of activity."

Ruoslahti et al., Science, Vol. 238, pp. 491-497, Oct. 23, 1987, discusscell adhesion proteins. They specifically state that "elucidation of theamino acid sequence of the cell-attachment domain in fibronectin and itsduplication with synthetic peptides establish the sequence Arg-Gly-Asp(RGD) as the essential structure recognized by cells in fibronectin."

Cheresh, Proc. Natl. Acad. Sci. USA, Vol. 84, pp. 6471-6475, September1987, describes the Arg-Gly-Asp-directed adhesion receptor involved inattachment to fibrinogen and the von Willebrand Factor.

Adams et al., U.S. Pat. No. 4,857,508, describes tetrapeptides whichinhibit platelet aggregation and the formation of a thrombus.

Tjoeng et at., EP 352,249, describe platelet aggregation inhibitorswhich antagonize interactions between fibrinogen and/or extracellularmatrix proteins and the platelet gpIIb/IIIa receptor, including8-guanido-octanoyl-Asp-2-(4-methoxyphenyl)ethyl amide.

Alig et al., EP 372,486, describe N-aryl beta-amino acids which inhibitfibrinogen, fibronectin and von Willebrand factor to the blood plateletfibrinogen receptor (glyco-protein Ilb/llIa).

Alig et al., EP 381,033, describe di-aryl or heteroaryl substitutedalkanoic acid derivatives of a defined formula which inhibit binding ofproteins to their specific receptors on cell surfaces, includingfibrinogen.

Alig et al., EP 384,362, describe glycine peptides of a specifiedformula containing an amidine group which inhibit binding of fibrinogento platelet fibrinogen receptors.

Horwell et al., EP 405,537, describe N-substituted cycloalkyl andpolycycloalkyl alpha-substituted Trp-Phe- and phenethylamine derivativeswhich are useful for treating obesity, hypersecretion of gastric acid inthe gut, gastrin-dependent tumors, or as antipsychotics.

It is an object of the present invention to provide fibrinogen receptorantagonists for use in inhibiting the binding of fibrinogen to bloodplatelets and inhibiting the aggregation of blood platelets. Anotheraspect of the present invention is to provide novel fibrinogen receptorantagonist compounds. Other objects of the present invention are toprovide methods of inhibiting the binding of fibrinogen to bloodplatelets and inhibiting the aggregation of blood platelets, through theadministration of novel fibrinogen receptor antagonist compounds. Theabove and other objects are accomplished by the present invention in themanner described below.

SUMMARY OF THE INVENTION

The present invention provides fibrinogen receptor antagonist compoundsof the formula: ##STR2## and their pharmaceutically acceptable salts,where D and E are independently chosen from C, N, O, and S;

X is chosen from ##STR3## and a 5- to 6- membered mono- or bicyclicaromatic or nonaromatic ring system containing 0, 1, or 2 heteroatomsselected from N, O, and S and either unsubstituted or substituted withR¹, R², R³, or R⁴, wherein R¹, R², R³ and R⁴ are independently selectedfrom the group consisting of hydrogen, C₁₋₁₀ alkyl, aryl C₀₋₈ alkyl,oxo, thio, amino C₀₋₈ alkyl, C₁₋₃ acylamino C₀₋₈ alkyl, C₁₋₆ alkylaminoC₀₋₈ alkyl, C₁₋₆ dialkylamino C₀₋₈ alkyl, C₁₋₄ alkoxy C₀₋₆ alkyl,carboxy C₀₋₆ alkyl, C₁₋₃ alkoxycarbonyl C₀₋₆ alkyl, carboxy C₀₋₆alkyloxy and hydroxy C₀₋₆ alkyl;

Y and A are independently chosen from ##STR4## where m and n areintegers independently chosen from 0-6; B is chosen from ##STR5## whereR⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are independently chosen from:

hydrogen, fluorine, C₁₋₈ alkyl, hydroxyl, hydroxy C₁₋₆ alkyl, carboxyC₀₋₆ alkyl, C₁₋₆ alkyloxy, C₃₋₈ cycloalkyl, aryl C₀₋₆ alkyl, C₁₋₆alkylcarbonyloxy, C₀₋₆ alkylamino C₀₋₆ alkyl, aryl C₀₋₆ alkylamino C₀₋₆alkyl, C₀₋₆ dialkylamino C₀₋₆ alkyl, aryl C₀₋₆ alkylcarbonyloxy, C₁₋₈alkylsulfonylamino C₀₋₆ alkyl, C₁₋₆ alkylaminocarbonyloxy, aryl C₀₋₆alkylaminocarbonyloxy, aryl C₀₋₈ alkylsulfonylamino C₀₋₆ alkyl, C₁₋₈alkyloxycarbonylamino C₀₋₈ alkyl, aryl C₀₋₈ alkyloxycarbonylamino C₀₋₈alkyl, C₁₋₈ alkylcarbonylamino C₀₋₆ alkyl, aryl C₀₋₆ alkylcarbonylaminoC₀₋₆ alkyl, C₀₋₈ alkylaminocarbonyl C₀₋₆ alkyl, aryl C₀₋₈alkylaminocarbonyl C₀₋₆ alkyl, C₀₋₈ alkylaminocarbonyl-amino C₀₋₆ alkyl,aryl C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl, C₀₋₈alkylaminosulfonylamino C₀₋₆ alkyl, aryl C₀₋₈ alkylaminosulfonylaminoC₀₋₆ alkyl, C₁₋₆ alkylsulfonyl C₀₋₆ alkyl, aryl C₀₋₆ alkylsulfonyl C₀₋₆alkyl, C₁₋₆ alkylcarbonyl C₀₋₆ alkyl, aryl C₀₋₆ alkylcarbonyl C₀₋₆alkyl, C₁₋₆ alkylthiocarbonylamino C₀₋₆ alkyl, and aryl C₀₋₆alkylthiocarbonylamino C₀₋₆ alkyl,

whereto groups may be unsubstituted or substituted with one or moresubstituents selected from R¹ and R², and ##STR6## where AA is an L- orD- amino acid, or its corresponding ester, connected through an amidelinkage;

R¹¹ is chosen from:

hydroxy, C₁₋₈ alkyloxy, aryl C₀₋₆ alkyloxy, C₁₋₈ alkylcarbonyloxy C₁₋₄alkyloxy, aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy, and an L- or D-aminoacid joined by an amide linkage and wherein the carboxylic acid moietyof said amino acid is as the free acid or is esterified by C₁₋₆ alkyl;and

R¹² is chosen from the group described by R¹.

Compounds of the invention are useful for inhibiting the binding offibrinogen to blood platelets and for inhibiting the aggregation ofblood platelets. The above-mentioned compounds can be used in a methodof acting upon a fibrinogen receptor which comprises administering atherapeutically effective but non-toxic amount of such compound to amammal, preferably a human. A pharmaceutical composition comprising apharmaceutically acceptable carrier and, dispersed therein, an effectivebut non-toxic amount of such compound is another feature of thisinvention.

DETAILED DESCRIPTION OF THE INVENTION

Fibrinogen receptor antagonist compounds of Formula I are useful in amethod of inhibiting the binding of fibrinogen to blood platelets andfor inhibiting the aggregation of blood platelets. Fibrinogen receptorantagonists of this invention are illustrated by compounds having theformula: ##STR7## and their pharmaceutically acceptable salts, where Dand E are independently chosen from C, N, O, and S;

X is chosen from: ##STR8## and a 5- to 6- membered mono- or bicyclicaromatic or nonaromatic ring system containing 0, 1, or 2 heteroatomsselected from N, O, and S and either unsubstituted or substituted withR¹, R², R³, or R⁴, wherein R¹, R², R³, and R⁴ are independently selectedfrom the group consisting of hydrogen, C₁₋₁₀ alkyl, aryl C₀₋₈ alkyl,oxo, thio, amino C₀₋₈ alkyl, C₁₋₃ acylamino C₀₋₈ alkyl, C₁₋₆ alkylaminoC₀₋₈ alkyl, C₁₋₆ dialkylamino C₀₋₈ alkyl, C₁₋₄ alkoxy C₀₋₆ alkyl,carboxy C₀₋₆ alkyl, C₁₋₃ alkoxycarbonyl C₀₋₆ alkyl, carboxy C₀₋₆alkyloxy, and hydrogen C₀₋₆ alkyl;

Y and A are independently chosen from ##STR9## where m and n areintegers independently chosen from 0-6; B is chosen from ##STR10## andtheir pharmaceutically acceptable salts, where R⁵, R⁶, R⁷, R⁸, R⁹, andR¹⁰ are independently chosen from:

hydrogen, fluorine, C₁₋₈ alkyl, hydroxyl, hydroxy C₁₋₆ alkyl, carboxyC₀₋₆ alkyl, C₁₋₆ alkyloxy, C₃₋₈ cycloalkyl, aryl C₁₋₆ alkyloxy, arylC₀₋₆ alkyl, C₁₋₆ alkylcarbonyloxy, C₀₋₆ alkylamino C₀₋₆ alkyl, aryl C₀₋₆alkylamino C₀₋₆ alkyl, aryl C₀₋₆ alkylcarbonyloxy, C₀₋₆ dialkylaminoC₀₋₆ alkyl, C₁₋₆ alkylaminocarbonyloxy, C₁₋₈ alkylsulfonylamino C₀₋₆alkyl, aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl, C₁₋₈alkyloxycarbonylamino C0-8alkyl, aryl C₀₋₈ alkyloxycarbonylamino C₀₋₈alkyl, C₁₋₈ alkylcarbonylamino C₀₋₆ alkyl, aryl C₀₋₆ alkylcarbonylaminoC₀₋₆ alkyl, C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl, aryl C₀₋₈alkylaminocarbonlyamino C₀₋₆ alkyl, C₀₋₈ alkylaminosulfonylamino C₀₋₆alkyl, aryl C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl, C₁₋₆ alkylsulfonylC₀₋₆ alkyl, aryl C₀₋₆ alkylsulfonyl C₀₋₆ alkyl, C₁₋₆ alkylcarbonyl C₀₋₆alkyl, aryl C₀₋₆ alkylcarbonyl C₀₋₆ alkyl, C₁₋₆ alkylthiocarbonylaminoC₀₋₆ alkyl, aryl C₀₋₆ alkylthiocarbonylamino C₀₋₆ alkyl, C₀₋₈alkylaminocarbonyl C₀₋₆ alkyl, and aryl C₀₋₈ alkylaminocarbonyl C₀₋₆alkyl,

wherein groups may be unsubstituted or substituted with one or moresubstituents selected from R¹ and R² ; and ##STR11## where AA is an L-or D-amino acid, or its corresponding ester, connected through an amidelinkage;

R¹¹ is chosen from

hydroxy, C₁₋₈ alkyloxy, aryl C₀₋₆ alkyloxy, C₁₋₈ alkylcarbonyloxy C₁₋₄alkyloxy, aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy, and an L- or D-aminoacid joined by an amide linkage and wherein the carboxylic acid moietyof said amino acid is as the free acid or is esterified by C₁₋₆ alkyl;and

R¹² is chosen from the group described by R¹.

A preferred embodiment of the present invention are the compounds##STR12## and the pharmaceutically acceptable salts, where D and E areindependently chosen from O, N, C and S;

X is chosen from ##STR13## or a 5- to 6- membered mono- or bicyclicnonaromatic ring system containing 0, 1, or 2 heteroatoms selected fromN, O, and S and either unsubstituted or substituted with R¹, R², R³ orR⁴, wherein R¹, R², R³ and R⁴ are independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, C₁₋₄ alkoxy C₀₋₆ alkyl, carboxyC₀₋₆ alkyl, C₁₋₃ alkoxycarbonyl C₀₋₆ alkyl, carboxy C₀₋₆ alkyloxy, andhydroxy C₀₋₆ alkyl;

Y and A are independently chosen from ##STR14## where m and n areintegers independently chosen from 0-6: B is chosen from ##STR15## whereR⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are independently chosen from:

hydrogen, fluorine C₁₋₈ alkyl, hydroxyl, hydroxy C₁₋₆ alkyl, carboxyC₀₋₆ alkyl, C₁₋₆ alkyloxy, C₃₋₈ cycloalkyl, aryl C₀₋₆ alkyl, C₁₋₆alkylcarbonyloxy, C₀₋₆ alkylamino C₀₋₆ alkyl, aryl C₀₋₆alkylcarbonyloxy, C₀₋₆ dialkylamino C₀₋₆ alkyl, C₁₋₆alkylaminocarbonyloxy, aryl C₁₋₆ alkylaminocarbonyloxy, C₁₋₈alkylsulfonylamino C₀₋₆ alkyl, aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl,C₁₋₈ alkyloxycarbonylamino C₀₋₈ alkyl, aryl C₀₋₈ alkyloxycarbonylaminoC₀₋₈ alkyl, C₁₋₈ alkylcarbonylamino C₀₋₆ alkyl, aryl C₀₋₆alkylcarbonylamino C₀₋₆ alkyl, C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl,aryl C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl, C₀₋₈alkylaminosulfonylamino C₀₋₆ alkyl, aryl C₀₋₈ alkylaminosulfonylaminoC₀₋₆ alkyl, C₁₋₆ alkylsulfonyl C₀₋₆ alkyl, aryl C₀₋₆ alkylsulfonyl C₀₋₆alkyl, C₁₋₆ alkylcarbonyl C₀₋₆ alkyl, aryl C₀₋₆ alkylcarbonyl C₀₋₆alkyl, C₁₋₆ alkylthiocarbonylamino C₀₋₆ alkyl, aryl C₀₋₆alkylthiocarbonylamino C₀₋₆ alkyl

wherein groups may be unsubstituted or substituted with one or moresubstituents selected form R¹ and R² ; and ##STR16## where AA is an L-or D-amino acid, or its corresponding ester, connected through an amidelinkage; and

R¹¹ is chosen from

hydroxy, C₁₋₈ alkyloxy, aryl C₀₋₆ alkyloxy, C₁₋₈ alkylcarbonyloxy C₁₋₄alkyloxy, aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy, and an L- or D-amino acid joined by an amide linkage and wherein the carboxylic acidmoiety of said amino acid is as the free acid or is esterified by C₁₋₆alkyl.

A more preferred embodiment of the present invention are the compounds##STR17## where D and E are independently chosen from C, N, O and S; Xis chosen from ##STR18## and a 5- to 6- membered mono- or bicyclicnonaromatic ring system containing 0, 1, or 2 heteroatoms selected fromN, O and S and either unsubstituted or substituted with R¹, R², R³ orR⁴, wherein R¹, R², R³ and R⁴ are independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, C₁₋₄ alkoxy C₀₋₆ alkyl,

Y and A are optional substituents that are independently chosen from##STR19## where m and n are integers independently chosen from 0-6; B is##STR20## where R⁷, R⁸, R⁹, and R¹⁰ are independently chosen from:

hydrogen, fluorine, C₁₋₈ alkyl, hydroxyl, hydroxy C₁₋₆ alkyl, carboxyC₀₋₆ alkyl C₁₋₆ alkyloxy, C₁₋₆ alkylcarbonyl, C₃₋₈ cycoalkyl, aryl C₀₋₆alkylcarbonyl, aryl C₀₋₆ alkyl, C₁₋₆ alkylcarbonyloxy, C₀₋₆ alkylaminoC₀₋₆ alkyl, aryl C₀₋₆ alkylcarbonyoxy, C₀₋₆ dialkylamino C₀₋₆ alkyl,C₁₋₆ alkylaminocarbonyloxy, C₁₋₈ alkylsulfonylamino C₀₋₆ alkyl, arylC₀₋₆ alkylsulfonylamino C₀₋₆ alkyl, C₁₋₈ alkylsulfonylamino C₀₋₆ alkyl,aryl C₀₋₈ alkyloxycarbonylamino C₀₋₈ alkyl, C₁₋₈ alkylcarbonylamino C₀₋₆alkyl, aryl C₀₋₆ alkylcarbonylamino C₀₋₆ alkyl, C₀₋₈alkylaminocarbonylamino C₀₋₆ alkyl, aryl C₀₋₈ alkylaminocarbonylaminoC₀₋₆ alkyl, C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl, aryl C₀₋₈alkylaminosulfonylamino C₀₋₆ alkyl, C₁₋₆ alkylsulfonyl C₀₋₆ alkyl, arylC₀₋₆ alkylsulfonyl C₀₋₆ alkyl, C₁₋₆ alkylcarbonyl C₀₋₆ alkyl, aryl C₀₋₆alkylcarbonyl C₀₋₆ alkyl, and C₁₋₆ alkylthiocarbonylamino C₀₋₆ alkyl;and

R¹¹ is chosen from

hydroxy, C₁₋₈ alkyloxy, and aryl C₀₋₆ alkyloxy.

The term "aryl" means a mono- or bicyclic system composed of 5- and 6-membered aromatic rings containing 0, 1, or 2 heteroatoms chosen from N,O or S.

The term "alkyl" means straight or branched alkane, alkene or alkyne.The term "alkoxy" includes an alkyl portion where alkyl is as definedabove.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion wherealkyl is as defined above and an aryl portion where aryl is as definedabove. The C_(0-n) or C_(1-n) designation, where n may be an integerfrom 1-10 or 2-10 respectively, refers to the alkyl component of thearylalkyl or alkylaryl unit.

The term "halogen" includes fluorine, chlorine, iodine and bromine.

The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur(S) atom. Under standard nomenclature used throughout this disclosure,the terminal portion of the designated side chain is described firstfollowed by the adjacent functionality toward the point of attachment.For example, a C₁₋₆ alkyl substituted with C₁₋₆ alkylcarbonylamino isequivalent to ##STR21## Most preferred compounds of the invention, withcorresponding IC₅₀ values for some of these in parentheses, are:

2-(Butylsulfonylamino)-3-{5[2'-(4-piperidin-4-yl-propyl)benzofuranyl]}propanoicacid (IC₅₀ =0.20 μM);

2-(Butylsulfonylamino)-3-{5[2'-(4-piperidin-4-yl-methyl)aminocarbonyl]benzofuranyl}propionicacid (IC₅₀ =6.6 μM);

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-N-carbobenzyloxyaminopropionicacid)carboxamide (IC₅₀ =0.067 μM);

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-N-butylsulfonylaminopropionicacid)carboxamide (IC₅₀ =0.036 μM);

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-S,S-dioxide-6-N-[3-(2(S)-N-butylsulfonylaminopropionicacid)carboxamide;

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2-(S)-N-Methylsulfonylaminopropionicacid)]carboxamide;

2-[2-(4-Piperidinyl)ethyl]benzimidazole-5-carbonyl-[2(S)-p-toluenesulfonylamino]-β-alanine;

2-[2-(4-Piperidinyl)ethyl]benzimidazole-5-carbonyl-[2(S)-butylsulfonylamion]-β-alanine(IC₅₀ =0.022 μM); and

5-[2-[4-Piperidinylethyl)oxy]-2-indolecarbonyl-2(S)-phenylsulfonylamion-.beta.-alanine(IC₅₀ =0.012 μM), and

2-[Z-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2-(S)-benzylureido)propionicacid]carboxamide.

The ADP-stimulated platelet aggregation assay was used to determine IC₅₀inhibition associated with compounds of the invention.

Human platelets were isolated from fresh blood, collected into acidcitrate/dextrose by differential centrifugation followed by gelfiltration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4)containing 2% bovine serum albumin. Platelet aggregation was measured at37° C. in a a Chronolog aggregometer. The reaction mixture containedgel-filtered human platelets (2×10⁸ per 1), fibrinogen (100 μg/ml), Ca²⁺(1 mM), and the compound to be tested. Aggregation was initiated byadding 10 uM ADP 1 minute after the other components had been added. Thereaction was allowed to proceed for at least 2 minutes. The extent ofinhibition of aggregation was expressed as the percentage of the rate ofaggregation observed in the absence of inhibitor. The IC₅₀ is the doseof a particular compound inhibiting aggregation by 50% relative to acontrol lacking the compound.

The abbreviations listed below are defined as Bn, benzyl; NMM,N-methylmorpholine; HOBt, 1-hydroxybenzotriazole; EDC,1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride; DMF,dimethylformamide; Pib, 4-(4-piperidyl)butanoyl; pTSA,paratoluenesulfonic acid; DMS, dimethylsulfide; TFA, trifluoroaceticacid; THF, tetrahydrofuran; DIBAL, diisobutylaluminum hydride; Boc (orBOC), tert-butoxycarbonyl; Cbz, benzyloxycarbonyl; Suc, succinoyl;alpine borane, β-isopinocamphenyl-9-borabicyclo[3.3.1 ]-nonane; TBDMS,tert-butyldimethylsilyl; Jones reagent, chromic acid; NBS,N-Bromosuccinimide; DEAD, diethyl azodicarboxylate; BPO, Benzoylperoxide; PPh₃, triphenyl phosphine; DMSO, Dimethylsulfoxide; Et₃ N,triethylamine; Tf₂ O, triflic anhydride; DMAP, 4-dimethylaminopyridine;BOP, benzotriazol-1-yloxytris(dimethylamino) phosphoniumhexafluorophosphate; PhCHO, benzaldehyde; and Boc₂ O,di-t-butyldicarbonate; dppp, 1,3-bis(diphenylphosphino)propane; TMSCHN₂,trimethylsilyl diazomethane; EtOAc, ethyl acetate; CH₂ Cl₂, methylenechloride; HOAc, acetic acid; CH₃ OH, methanol; CHCl₃, chloroform; AA isan L- or D-amino acid chosen from naturally occurring amino acidsglycine, alanine, valine, isoleucine, leucine, serine, threonine,proline, aspartic acid, glutamic acid, lysine, arginine, asparagine,glutamine, cysteine, methionine, tryptophan, phenylalanine, tyrosine,and histidine.

Unless otherwise indicated, all degree values are Celsius.

2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl iodide, (3-2), used inScheme 3, is prepared by according to the following procedure.

4-Piperidine-2-ethanol (Aldrich) (130 g, 1.0 mole) was dissolved in 700mL dioxane, cooled to 0° C. and treated with 3N NaOH (336 mL, 1.0 mole),and di-t-butyldicarbonate (221.8 g, 1.0 mole). The ice bath was removedand the reaction stirred overnight. The reaction was concentrated,diluted with water and extracted with ether. The ether layers werecombined, washed with brine, dried over MgSO₄, filtered and evaporatedto give Boc-4-piperidine-2-ethanol. R_(f) =0.37 in 1:1 EtOAc/Hexanes,ninhydrin stain

¹ H NMR (300 MHz, CDCl₃)δ4.07 (bs, 2H), 3.7 (bs, 2H), 2.7 (t,J=12.5 Hz,2H), 1.8-1.6 (m, 6H), 1.51 (s, 9H), 1.1 (ddd, J=4.3, 12.5, 12 Hz, 2H).

Boc-4-piperidine-2-ethanol (10.42 g, 0.048 mole was dissolved in 400 mlbenzene and imidazole (4.66 g, 0.068 moles) and triphenylphosphine(15.24 g, 0.05 moles) were added at room temperature. After 6 hours thereaction mixture was filtered and the filtrate was evaporated to give adark residue. This was purified by flash chromatography on silica geleluting with 10%-EtOAc-hexanes to give Boc-4-piperidine-2-ethyl iodideas a yellow oil.

The alcohol 1-1 is prepared according to Example 18, pages 21-22, up toline 21, of EP 478 328, prior to THF and triphenylphosphine treatment.

The pharmaceutically acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quarternary ammoniumsalts of the compounds of Formula I formed, e.g., from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula I which contain a basic oracidic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formula I are alsoreadily prepared by conventional procedures such as treating an acid ofFormula I with an appropriate amount of a base, such as an alkali oralkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium,or magnesium, or an organic base such as an amine, e.g.,dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine,benzylamine and the like, or a quaternary ammonium hydroxide such astetramethylammonium hydroxide and the like.

The compounds of Formula I are useful in inhibiting the binding offibrinogen to blood platelets, inhibiting aggregation of bloodplatelets, treatment of thrombus formation or embolus formation, and inthe prevention of thrombus formation or embolus formation. Thesecompounds are useful as pharmaceutical agents for mammals, especiallyfor humans. The compounds of this invention may be administered topatients where prevention of thrombosis by inhibiting binding offibrinogen to the platelet membrane glycoprotein complex IIb/IIIareceptor is desired. Compounds of this invention may also be used toprevent or modulate the progress of myocardial infarction, unstableangina and thrombotic stroke, in either acute or chronic settings. Inaddition, they may be useful in surgery on peripheral arteries (arterialgrafts, carotid endarterectomy) and in cardiovascular surgery wheremanipulation of arteries and organs, and/or the interaction of plateletswith artificial surfaces, leads to platelet aggregation and consumption.The aggregated platelets may form thrombi and thromboemboli. Compoundsof this invention may be administered to surgical patients to preventthe formation of thrombi and thromboemboli.

Extracorporeal circulation is routinely used for cardiovascular surgeryin order to oxygenate blood. Platelets adhere to surfaces of theextracorporeal circuit. Adhesion is dependent on the interaction betweengpIIb/IIIa on the platelet membranes and fibrinogen adsorbed to thesurface of the circuit. (Gluszko et al., Amer. J. Physiol., 1987, 252:H,pp 615-621). Platelets released from artificial surfaces show impairedhemostatic function. Compounds of this invention may be administered toprevent adhesion.

Other applications of these compounds include prevention of plateletthrombosis, thromboembolism, reocclusion, and restenosis during andafter thrombolytic therapy and prevention of platelet thrombosis,thromboembolism, reocclusion and restenosis after angioplasty ofcoronary and other arteries and after coronary artery bypass procedures.

The compounds of Formula I may be administered to mammals, preferably incombination with pharmaceutically-acceptable carriers or diluents,optionally with known adjuvants such as alum, in a pharmaceuticalcomposition which is non-toxic and in a therapeutically effectiveamount, according to standard pharmaceutical practice. The compounds canbe administered orally or parenterally, including intravenous,intramuscular, intraperitoneal, trans-dermal, subcutaneous and topicaladministration.

For oral use of a fibrinogen receptor antagonist according to thisinvention, the selected compounds may be administered, for example, inthe form of tablets or capsules, or as an aqueous solution orsuspension. In the case of tablets for oral use, carriers which arecommonly used include lactose and corn starch, and lubricating agents,such as magnesium stearate, are commonly added. For oral administrationin capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added.

For intramuscular, intraperitoneal, subcutaneous, and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment and prevention of diseases related to plateletaggregation, fibrin formation, and thrombus and embolus formation,comprising the administration of a therapeutically effective butnon-toxic amount of the compounds of Formula I, with or withoutpharmaceutically acceptable carriers or diluents.

Compositions of this invention include fibrinogen receptor antagonistcompounds of this invention in combination with pharmacologicallyacceptable carriers, e.g. saline, at a pH level e.g. 7.4, suitable forachieving inhibition of platelet aggregation. The compositions may alsobe combined with anticoagulants such as heparin or warfarin. Thecompositions may also be combined with thrombolytic agents such asplasminogen activators or streptokinase in order to inhibit plateletaggregation in more acute settings. The composition may further becombined with antiplatelet agents such as aspirin. The compositions aresoluble in an aqueous medium, and may therefore be effectivelyadministered in solution.

When a compound according to Formula I is used as a fibrinogen receptorantagonist in a human subject, the daily dosage will normally bedetermined by the prescribing physician with the dosage generallyvarying according to the age, weight, and response of the individualpatient, as well as the severity of the patients symptoms.

In one exemplary application, a suitable amount of compound isadministered orally to a heart attack victim subsequent to angioplasty.Administration occurs subsequent to angioplasty, and is in an amountsufficient to inhibit platelet aggregation, e.g. an amount whichachieves a steady state plasma concentration of between about 0.01-100μM preferably between about 0.1-50 μM.

The present invention also includes a pharmaceutical compositioncomprising compounds of the present invention in combination with tissuetype plasminogen activator or streptokinase. The invention also includesa method for promoting thrombolysis and preventing reocclusion in apatient which comprises administering to the patient an effective amountof compositions of the invention.

The present invention provides a method of inhibiting the binding offibrinogen to blood platelets, inhibiting aggregation of bloodplatelets, treating thrombus formation or embolus formation, and inpreventing thrombus formation or embolus formation in a mammal,comprising the administration of a therapeutically effective butnontoxic amount of the compounds of this invention, with or withoutpharmaceutically acceptable carriers or diluents.

The present invention still further provides a method of inhibiting thebinding of fibrinogen to blood platelets, inhibiting aggregation ofblood platelets, treating thrombus formation or embolus formation, andin preventing thrombus formation or embolus formation in a mammal,comprising the administration of a therapeutically effective butnon-toxic mount of the compounds of this invention in combination withthrombolytic agents, such as tissue plasminogen activators orstreptokinase, anticoagulants such as heparin or warfarin, orantiplatelet agents such as aspirin, with or without pharmaceuticallyacceptable carriers or diluents.

The compounds of Formula I are prepared according to the reactionschemes set forth below. ##STR22##

4-(N-t-Butyloxycarbonylpiperidin-4-yl)butanal(1-2)

A solution of oxalyl chloride (8.48 moles) in CH₂ Cl₂ (60 ml) cooled to-70° was treated with DMSO (11.27 mmoles) and this was stirred for 15min. A solution of 1-1 (1.45 g, 5.63 mmoles) was added and the resultingmixture stirred for 2 hrs at -70°. Then, triethylamine (28.7 mmoles) wasadded and the reaction mixture was stirred for 2.0 hrs.

The reaction mixture was washed in H₂ O, 10% KHSO₄ solution, H₂ O, brineand dried (Na₂ SO₄). Solvent removal gave 1-2 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ1.10 (2H,m), 1.23-1.40 (4H,m), 1.45 (9H,s),1.58-1.74 (4H,m), 2.43 (2H,dt), 2.68 (2H,dt), 4.09 (2H,bd), 9.78 (1H,s).

5-(N-t-Butyloxycarbonylpiperidin-4-yl)-1,1-dibromo-pent-1-ene (1-3)

A solution of CBr₄ (3.45 g, 10.42 mmol) in CH₂ Cl₂ (40 ml) was cooled to0° and treated with Ph₃ P (5.46 g, 20.8 mmol) with stirring for 1.5 hrs.Reaction mixture was then cooled to -70° and treated with 1-2 (1.29 g,5.08 mmol) in CH₂ Cl₂ (10 ml) and this was stirred for 0.5 hr.

The reaction was then quenched with Et₃ N (4 ml), warmed to roomtemperature and poured into hexane (500 ml). The suspension was filteredand the filtrate concentrated to provide a residue that was purified byflash chromatography on silica gel eluting with hexane (15)/EtOAc (1) togive pure 1-3.

¹ H NMR (300 MHz, CDCl₃) β1.08 (2H,m), 1.20-1.40 (4H,m), 1.45 (9H,s),1.62 (2H,bd), 2.08 (2H,m), 2.67 (2H,t), 4.06 (2H,d), 6.39 (1H,t)

5-(N-t-Butyloxycarbonylpiperidin-4-yl)pent-1-yne (1-4)

A solution of 1-3 (1.70 g, 4.13 mmol) in THF (80 ml) was cooled to -78°and treated with n-BuLi (4.25 mmol) with stirring for 15 min. Thereaction was then quenched with 10% KHSO₄ (25 ml) and the solvent wasremoved. The residue was taken up in Et₂ O (150 ml) and this was washedwith 10% KHSO₄ solution, brine, and dried (Na₂ SO₄).

Solvent removal gave 1-4 as an oil.

¹ H NMR (300 MHz, CDCl₃) δ1.10 (2H,m), 1.20-1.40 (4H,m), 1.47 (9H,s),1.55 (1H,m), 1.64 (2H,bd), 2.08 (1H,q), 2.20 (1H,dt), 2.68 (2H,dt), 4.08(2H, bd), 6.39 (1H,t).

Methyl 2(S)-(Butylsulfonylamino)-3-(4-hydroxy-3-iodo)-phenylpropionate(1-5)

A solution of 1-6 (3-iodo-L-tyrosine (Aldrich) was converted to 1-6 bytreatment with SOCl₂ /MeOH in the normal fashion) (10.5 g, 0.033 mol) inCH₃ CN (150 ml) was treated with pyridine (0.039 mol) and butanesulfonylchloride (0.039 mmol) and the resulting mixture was heated at 60° for 2days.

The solvent was removed and the residue was taken up in 10% KHSO₄ solnand extracted with EtOAc. The organic extract was dried and the solventremoved to give 1-5.

¹ H NMR (300 MHz, CDCl₃) δ0.90 (3H,t), 1.35 (1H,m), 1.61 (2H,m), 2.78(2H,m), 2.89 (1H,m), 3.08 (1H,dd), 3.78 (3H,s), 4.29 (1H,m), 5.10(1H,m), 5.98 (1H,m) 6.89 (1H,d), 7.08 (1H,d), 7.50 (1H,m).

Methyl2(S)-(Butylsulfonylamino)-3-{5-[2'-3-(N-t-butyloxycarbonyl-piperidin-4-ylpropyl)benzofuranyl]}-proionate(1-7)

A solution of 1-5 (0.485. g, 1.14 mmol) in diethylamine (10 ml) wastreated with Pd (Ph₃ P)₂ Cl₂ (0.04 g), cuprous iodide (5.5 mg) and 1.4(0.34 g, 1.37 mmol) and the resulting mixture was stirred at rt for 72hrs.

The solvent was removed and the residue purified by flash chromatographyin silica gel eluting with hexane (80)/EtOAc (20) to give pure 1-7.

¹ H NMR (300 MHz, CDCl₃) δ0.77 (t,J=7.3 Hz, 3H), 1.05-1.42 (m, 9H), 1.44(s, 9H), 1.48-1.77 (m,4H), 2.68 (m, 6H), 3.04 (dd,J=7.6, 13.8 Hz, 1H),3.23 (dd,J=5.1, 13.8 Hz, 1H), 3.77 (s, 3H), 4.07 (bs, 2H), 4.35(dd,J=5.1, 7.6 Hz, 1H), 4.5 (bs, 1H), 6.32 (s, 1H), 6.98 (m, 1H), 7.25(m, 3H).

2(S)-(Butylsulfonylamino)-3-{5-[2'-3-(piperidin-4-ylpropyl)benzofuranyl]}propionicacid (1-8)

A solution of 1-7 (0.18 g, 0.33 mmol) in CHCl₃ (20 ml) was treated withTMSI at room temperature. After 15 minutes 10 ml CH₃ OH was added, andthe solvent was then removed. The residue was taken up in THF (1)/MeOH(1)/H₂ O (1) (12 ml/and LiOH.H₂ O (0.138 g, 3.28 mmol) was added. After2 hours at room temperature the solvent was removed and the residue waspurified by flash chromatography on silica gel eluting with EtOH(9)/NH₄OH(1)/H₂ O(1) to give pure 1-8.

¹ H NMR (300 MHz, CD₃ OD) δ0.78 (t,J=7.3 Hz, 3H), 1.06-1.6 (m, 10H),1.78 (m,2H), 1.85 (bd, J=14.5 Hz, 2H), 2.68 (m, 2H), 2.75 (m,2H), 2.85(m, 2H), 2.90 (dd, J=8.3, 13.6 Hz, 1H), 3.20 (dd, J=4.8, 13.6 Hz, 1H),3.30 (m, 2H), 3.97 (dd, J=4.8, 8.3 Hz, 1H), 6.41 (s, 1H), 7.16 (dd,J=1.8, 8.1 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H) 7.4 (d, J=1.7 Hz, 1H).##STR23##

Methyl2(S)-(Butylsulfonylamino)-3-{5-[2'-(hydroxymethyl)]benzofuranyl}propionate(2-1)

Propargyl alcohol (2.05 mmol) was dissolved in Et₂ NH (5 ml) and treatedwith 1-5 (0.83 g, 1.95 mmol), Pd(PPh₃)₂ Cl₂ (0.060 g) and CuI (0.009 g)and the resulting mixture was stirred at room temperature for 4 days.The solvent was removed and the residue purified by flash chromatographyon silica gel eluting with hexane (6)/EtOAc(4) to give pure 2-1.

¹ H NMR (300 MHz, CDCl₃) δ0.80 (3H,t), 1.23 (2H,m), 2.58 (2H,m), 2.00(1H,m), 2.71 (2H,t), 3.03-3.30 (2H,m), 3.77 (3H,s), 4.40 (1H,m), 6.60(1H,s), 7.07 (1H,d), 7.38 (2H,m).

Methyl2(S)-(Butylsulfonylamino)-3-{5-[2'-(formyl)-benzofuranyl]}propionate(2-2)

A solution of 2-1 (0.050 g, 0.0135 mmol) in CH₂ Cl₂ (50 ml) was treatedat room temperature with CrO₃ /pyridine (0.081 mmol CrO₃ in 10 ml CH₂Cl₂ containing 0.63 pyridine). After 1.0 hour the solvent was removedand the residue purified by flash chromatography on silica gel elutingwith hexane (1)/EtOAc (1) to give pure 2-2.

¹ H NMR (300 MHz, CDCl₃) δ0.80 (3H,t), 1.23 (2H,m), 1.57 (2H,m), 2.77(2H,m), 3.21 (2H,m), 3.79 (3H,s), 4.40 (1H,m), 5.02 (1H,m), 7.35(1H,dd), 7.58 (3H,m), 9.87 (1H,s),

Methyl2(S)-(Butylsulfonylamino)-3-{5-[2'-(carboxy)benzofuranyl]}propionate.(2-3)

A solution of 2-2 (0.135 g, 0.0367 mmol) in acetone (10 ml) was treatedwith CrO₃ /H₂ SO₄ reagent dropwise. After 10 minutes the orange colorhad disappeared and the reaction was greenish. After 0.5 hr saturatedNaHCO₃ soln was added to pH=9 and this was extracted in EtOAc. Theaqueous phase was then acidified to pH 2-3 with 10% KHSO₄ solution andextracted with EtOAc. The organic extract was dried (Na₂ SO₄) and thesolvent removed to give 2-3.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (3H,t), 1.33 (2H,m), 1.70 (2H,m), 2.93(2H,m), 3.26 (2H,m), 3.84 (3H,s), 4.55 (1H,bs), 5.75 (1H,bs), 7.22(1H,m), 7.40 (1H,bs), 7.52 (2H,bs).

Methyl2(S)-(Butylsulfonylamino)-3-{5-[2'-(4-N-carbobenzyloxypiperidinylmethyl)aminocarbonyl]benzofuranyl}propionate(2-4)

A solution of 2-3 (0.11 g, 0.29 mmol) in CH₂ Cl₂ (10 ml) was cooled to0° and treated with N-methylmorpholine (0.057 mmol) followed by isobutylchloroformate (0.032 mmol). After stirring at 0° for 10 minutesN-CBZ-(4-aminomethyl)piperidine (2-6) (0.078 g, 0.032 mmoles) was addedand reaction was stirred for 1.0 hr. The reaction mixture was quenchedwith pH 7 buffer and extracted with CH₂ Cl₂. The organic phase waswashed with 10% KHSO₄, brine, dried (Na₂ SO₄) and the solvent wasremoved to provide 2-4.

¹ H NMR (300 MHz, CDCl₃) δ0.80 (3H,t), 1.23 (4H,m), 1.58 (2H,m), 1.80(3H,m), 2.75 (4H,m), 3.07-3.30 (2H,m), 3.57 (2H,m) 3.76 (3H,s) 4.22(2H,m), 4.38 (1H,m), 4.96 (1H,d), 5.10 (1H,s) 6.75 (1H,t), 7.21-7.50(9H,m). ##STR24##

N-CBZ-(4-Aminomethyl)piperidine (2-6)

A solution of 4-(aminomethyl)piperidine (Aldrich) (5.0 g, 0.0438 mol) inCH₂ Cl₂ (100 ml) was cooled to -78° and treated with CBZ-Cl (Aldrich)(0.022 mol) dropwise. The reaction mixture was stirred at -78° C. for0.5 hr and then allowed to warm to 0° over 1 hour. The reaction mixturewas filtered and the solution concentrated to give a residue that waspurified by flash chromatography on silica gel eluting with 5%MeOH/CHCl₃ +1% Et₃ N to give pure 2-6.

¹ H NMR (300 MHz, CDCl₃) δ1.1 (2H, m), 1.4 (3H, m), 1.7 (2H, bd), 2.57(2H, d), 2.75 (2H, bt), 4.2 (2H, bs), 5.11 (2H, s), 7.2-7.4 (5H, m)

2(S)-(Butylsulfonylamino)-3-{5-[2'-(4-piperidinylmethyl)aminocarbonyl]benzofuranyl}propionic acid (2-5)

A soln of 2-4 (0.13 g, 0.21 mmol) in CH₂ Cl₂ (10 ml) was treated withTMSI (2.5 mmol) at room temperature for 0.5 hr. Methanol (5 ml) was thenadded with stirring and the solvent was removed. The residue was takenup in THF (1)/MeOH (1)/H₂ O (1) (12 ml) and LiOH.H₂ O (0.088 g, 2.1mmol) was added. After stirring for 1.0 hr. at room temperature thesolvent was removed and the residue was purified by flash chromatographyon silica gel eluting with EtOH(1)/H₂ O (1)/MeOH (1) to give pure 2-5.

¹ H NMR (300 MHz, CD₃ OD) δ0.82 (t, J=7.3 Hz, 3H), 1.26 ((m, 2H),1.4-1.6 (m, 4H), 2.0 (bd, 14.5 Hz, 3H), 2.8 (m, 2H), 3.0 (m, 3H), 3.20(m, 1H), 3.3-3.5 (m, 4H), 3.99 (dd, J=4.8, 7.9 Hz, ¹ H), 7.3-7.5 (m,3H), 7.6 (s, 1H). ##STR25##

2-[2-(n-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6carboxylicacid (3-3)

A solution of benzothiophene-6-carboxylic acid (1.78 g, 0.01 mol) in THF(140 ml) cooled to -75° was treated with n-BuLi (0.02 mol) dropwise andthe resulting solution was stirred at -70° for 1 hr. Then, a solution of2-(N-t-Butyloxycarbonylpiperidin- 4-yl)ethyl iodide (3.39 g, 0.01 mol)in THF (10 ml) was added dropwise followed by HMPA (1.79 g, 0.01 mol).The resulting solution was stirred at -70° for 4 hrs and then at 23° for16 hrs. The cooled reaction was quenched with 10% KHSO₄, the solventremoved, and the residue was taken up in H₂ O (150 ml) and extractedwith EtOAc. The solvent was removed and the residue was purified byflash chromatography on silica gel eluting with CHCl₃ (97)/MeOH (2)/HOAC(1) to give a solid which was identified to be a mixture of 3-1 and 3-3.

These were separated to by a sequence that involved conversion to themethyl ester, column chromatography [(silica, hexane(4)/EtOAC (1)], andhydrolysis (LiOH.H₂ O) to give pure 3-3.

¹ H NMR (300 MHz, CDCl₃) δ1.20 (3H, m), 1.42 (9H, s), 1.50 (2H, m), 1.72(4H, m) 2.68 (2H, m), 2.97 (2H, m, 4.12 (2H, m), 7.09 (1H, s), 7.72 (1H,d), 8.05 (1H, d).

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6-N-[3(methyl2(S)-N-carbobenzyloxyaminopropionate)]carboxamide (3-4)

A solution of 3-3 (0.44 g, 0.0011 mol), 5-2 (0.329 g, 0.0014 mol), andHOBT (0.17 g, 0.0012 mol) in DMF (20 ml) at ambient temperature wastreated with N-methylmorpholine (NMM), (0.34 g, 0.0034 mol) followed byEDC (0.25 g, 0.0013 mol). After stirring overnight, the solvent wasremoved and the residue was taken up in EtOAc (200 ml) and washed with10% KHSO₄ solution, brine, saturated NaHCO₃ solution and dried (NaSO₄).The solvent was removed and the residue purified by flash chromatographyon silica gel eluting with hexane(55)/EtOAc(45) to give pure 3-4 as asolid.

R_(f) 0.35, silica, hexane(1)/EtOAc(1)

¹ H NMR (300 MHz, CDCl₃) 1.20 (2H,m), 1.43 (9H,s), 1.50 (2,H,m), 1.73(4H, m), 2.75 (2H,bt), 2.95 (2H,t), 3.78 (2H,s), 3.89 (2H,m), 4.08(2H,m), 4.56 (1H,m), 5.11 (2H,s), 5.96 (1H,d), 7.03 (1H,s), 7.31 (2H,m),7.63 (1H,m).

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-N-carbobenzyloxyaminopropionicacid)]carboxamide (3-5)

A solution of 3-4 (0.12 g, 0.19 mmol) in THF (1)/MeOH (1)/H₂ O (1) (10ml) was treated at 23° with LiOH.H₂ O (0.024 g, 0.58 mmol) for 18 hrs.The solvent was removed and the residue was taken up in H₂ O (50 ml),acified to pH 2-3 with 10% KHSO₄ soln, and extracted with EtOAc. Theextract was dried (Na₂ SO₄), the solvent removed, and the residuepurified by flash chromatography on silica gel eluting with CHCl₃(95)/MeOH(5)/HOAC (1) to give the desired acid, R_(f) 0.25 (silica,CHCl₃ (95)/MeOH(5)/HOAC (1). This acid was dissolved in EtOAc (25 ml),cooled to -25° and treated with HCl (g) for 15 min and then stirred at0° for 1 hr. The solvent was removed and the residue was trituated withEtOAc to give pure 3-5. R_(f) 0.3 [(silica, EtOH(9)/H₂ O(1)/NH₄ OH (1)].##STR26##

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6-N-[3-(Methyl2(S)-butylsulfonylaminopropionate)]carboxamide (4-1)

A solution of 3-3 (0.58 g, 0.0015 mol), 5-6 (0.41 g, 0.0015 mol) andHOBT (0.22 g, 0.0016 mol) in DMF (20 ml) was treated at room temperaturewith NMM (0.45 g, 0.0045 mol) followed by EDC (0.348, 0.00175 mol) andthe resulting mxt. was stirred for 16 hrs.

The solvent was removed, and the residue was diluted with H₂ O (150 ml)and extracted with EtOAc. The organic extract was washed with 10% KHSO₄solution, brine, saturated NaHCO₃ solution and dried (NaSO₄). Solventremoval provided a residue that was purified by flash chromatography onsilica gel eluting with CHCl₃ (98)/ MeOH (2) to give pure 4-1. R_(f)0.25, silica, CHCl₃ (98)/MeOH (2).

¹ H NMR (300 MHz, CDCl₃) δ0.90 (3H, t), 1.18 (2H, m), 1.39 (2H, t), 1.45(9H, s), 1.50 (2H, m), 1.58-1.85 (6H, m), 2.67 (2H, bt), 2.95 (2H t),3.03 (2H, m), 3.83 (3H,s), 3.92 (1H, m), 4.09 (2H, m), 4.36 (1H, m),5.63 (1H, d), 6.85 (1H, t), 7.02 (1H, s), 7.68 (1H, s), 8.25 (1H, s).

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-butysulfonylaminopropionic acid)]carboxamide (4-2)

4-1 (0.054 g, 0.0031 mol) was treated with LiOH.H₂ O as described for2-5 to give 4-2. R_(f) 0.2, silica, CHCl₃ (95)/MeOH (5).

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-butylsulfonylaminopropionicacid)]carboxamide (4-3)

4-2 (0.23 g) was dissolved in EtOAc and treated with HCl (g) asdescribed for 3-6 to give 4-3, R_(f) 0.3, silica, EtOH(9)/H₂ O(1)/NH₄OH(1)

¹ H NMR (300 MHz, CD₃ OD) δ0.87 (3H, t), 1.38 (4H, m), 1.75 (5H, m),2.02 (3H, m), 3.00 (6H, m), 3.38 (2H, bd), 3.60 (1H, m), 3.85 (1H, dd),4.34 (1H, m), 7.18 (1H, s), 7.77 (2H, m), 8.30 (1H, s).

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-S,S-dioxide-6-N-[3-(Methyl2(S)-butylsulfonylaminopropionate)]carboxamide (4-4)

A solution of m-chloroperbenzoic acid (0.216 g, 0.001 mol) in CH₂ Cl₂(10 ml) at room temperature was treated with 4-1 (0.24 g, 0.4 mmol) andthe resulting solution was stirred for 3 hrs. This was diluted with CH₂Cl₂ (100 ml), washed with H₂ O, saturated NaHCO₃ solution, brine anddried (Na₂ SO₄). The solvent was removed and the residue purified bychromatography on silica gel eluting with hexane(35)/EtOAc(65) to give4-4, R_(f) 0.35, silica, hexane(35)/EtOAc (65).

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-S,S-dioxide-6-N-[3-(2(S)-N-butylsulfonylaminopropionicacid)]carboxamide (4-5)

4-4 (0.25 g, 0.39 mmol) was treated with LiOH.H₂ O as described for 3-5to provide the desired acid, R_(f) 0.3, silica, CHCl₃ (90)/CH₃OH(9)/HOAc(1). This acid was dissolved in EtOAc and treated with HCl (g)as described for 3-6 to give 4-5, R_(f) 0.25 [(silica, EtOH(10)/NH₄OH(1)/H₂ O (1)].

¹ H NMR (300 MHz, CD₃ OD) δ0.76 (3H, t), 1.23 (1H, t), 1.40 (4H, m),1.78 (5H, m), 2.03 (2H, m), 2.67 (2H, t), 3.04 (4H, m), 3.40 (1H, db),3.61 (1H, m), 4.09 (1H, m), 4.26 (1H, m), 7.18 (1H, s), 7.55 (1H, d),8.10 (1H, dd), 8.16 (1H, d). ##STR27##

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6-N-(3-[methyl2(S)-N-methylsulfonylaminopropionate)]carboxamide (4-6)

3-3 (0.234 g, 0.6 mmol) as treated with 5-7 (0.14 g, 0.6 mmol) asdescribed for 4-2 to provide crude 4-6 which was purified by flashchromatography on silica gel eluting with hexane(60)/acetone(40) toprovide pure 4-6. R_(f) 0.4, silica, hexane(60)/acetone (40).

¹ H NMR (300 MHz, CDCl₃) δ1.15 (2H, m), 1.28 (1H, m), 1.45 (9H, s), 1.73(4H, m), 2.68 (2H, bt), 2.93 (2H, t), 3.00 (3H, s), 3.82 (3H, s), 3.95(1H, m), 4.08 (2H, m), 4.39 (1H, m), 5.82 (1H, d), 6.87 (1H, t), 7.02(1H, s), 7.68 (2H, s), 8.23 (1H, s). ##STR28##

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-methylsulfonylaminopropionic acid)]carboxamide (4-7)

4-6 (0.24 g, 0.42 mmol) was treated with LiOH.H₂ O (0.053 g, 1.27 mmol)as described for 4-1 to provide pure 4-7. R_(f) 0.2, silica, CHCl₃(95)/MeOH (5).

¹ H NMR (300 MHz, CDCl₃) δ1.12 (2H, m), 1.45 (9H, s), 1.64 (4H, m), 2.63(2H, bt), 2.89 (2H, m), 2.91 (3H, s), 3.80 (1H, m), 3.90 (1H, m), 4.07(2H, m), 4.36 (1H, m), 6.22 (1H, m), 6.95 (1H, s), 7.40 (1H, m), 7.60(1H, d), 7.66 (1H, d), 8.20 (1H, s). ##STR29##

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-methylsulfonylaminopropionicacid)]carboxamide (4-8)

4-7 (0.21 g, 3.79 mmol) was dissolved in EtOAc (25 ml) and treated withHCl (g) at -25° as described for 4-3 to give pure 4-8. R_(f) 0.45,silica, EtOH(10)/conc NH₄ OH(1)/H₂ O(1).

Calc. for C₂₀ H₂₇ N₃ O₅ S₂.HCl: C, 49.02; H, 5.76; N, 8.57.

Found: C, 48.73; H, 6.00; N, 8.27. ##STR30##

Methyl 2(S)-benzyloxycarbonylamino-3-aminopropionatehydrochloride (5-2)

To a cooled suspension of 2(S)-benzyloxycarbonylamino-3-aminopropionic(Fluka) acid (5-1) (10 g, 0.042 mol) in 150 ml of methanol was added5.47 g (0.046 mol) of thionyl chloride over 20 minutes. The resultingsolution was allowed to stir at room temperature overnight. After ˜18hrs, the solvent was removed in vacuo, and the residual solid wasstirred with 150 ml of ether for 0.5 hr. The resulting white solid wascollected and air dried to give 5-2.

¹ H NMR (300 MHz, CD₃ OD) δ3.26 (2H, m), 3.45 (1H, dd), 3.77 (3H, s),4.25 (1H, m), 5.13 (2H, s), 7.37 (5H, m).

Methyl2(S)-benzyloxycarbonylamino-3-(N-t-butyloxycarbonyl)aminopropionate(5-3)

To a 2-phase mixture of CH₂ Cl₂ (500 ml) and saturated NaHCO₃ solution(300 ml) was added 28.87 g (0.10 mol) of 5-2. After a few minutes, 21.83g (0.10 mol) of di-t-butyldicarbonate was added in one portion and theresulting mixture was stirred at room temperature for 4 hrs. The CH₂ Cl₂layer was then separated from the aqueous layer, and the aqueous layerwas extracted with 300 ml of CH₂ Cl₂. The combined organic extracts werewashed with brine, dried and the solvent removed in vacuo to provide theproduct as a viscous oil. Trituration of this oil with 300 ml of hexanegave 5-3 as a white solid, m.p. 85°-87°.

¹ H NMR (300 MHz, CDCl₃) δ1.42 (9H, s), 1.50 (4H, m), 1.62 (1H, m), 3.52(2H, m), 3.75 (3H, s), 4.41 (1H, m), 4.83 (1H, m), 5.12 (2H, s), 5.78(1H, m), 7.35 (5H, m).

Methyl 2(S)-amino-3-(N-t-butyloxycarbonyl)aminopropionate (5-4)

To a solution of 6.60 g (0.0187 mol) 5-3 in 150 ml EtOH was added 0.5 gof 10% Pd/C. The resulting mixture was hydrogenated under balloonpressure at r.t. for 4 hrs. The catalyst was filtered off and thesolvent removed in vacuo to provide 5-4 as a viscous oil.

¹ H NMR (300 MHz, CDCl₃) δ1.45 (9H, s), 1.49 (2H, m), 1.59 (2H, m), 3.25(1H, m), 3.49 (1H, m), 3.58 (1H,m), 3.75 (3H, s), 5.03 (1H, m)

Methyl 2(S)-butylsulfonylamino-3-(N-t-butylcarbonyl)aminopropionate(5-5)

To a solution of 0.400 g (0.00183 mol) of 5-4 in 10 ml of CH₃ CN wasadded 0.226 g (0.00286 mol) pyridine followed by 0.408 g (0.0026 mol) ofn-butanesulfonyl chloride. The resulting solution was stirred at roomtemperature for 2.5 hrs at which time starting material was consumed.The solvent was removed in vacuo and 50 ml of H₂ O added to the residualmaterial. This mixture was extracted with 3×50 ml portions of ethylacetate and the combined extracts washed with brine, dried (Na₂ SO₄),filtered and concentrated to give 0.5 g of a viscous oil. Trituration tothis oil with 25 ml of hexane provided 5-5 as a white, amorphous solid.

¹ H NMR (300 MHz, CDCl₃) δ0.95 (3H, t), 1.43 (9H, s), 1.48 (2H, m), 1.80(2H, m), 3.03 (2H, m), 3.52 (2H, t), 3.80 (3H, s), 4.22 (1H, m), 4.99(1H, bt), 5.48 (1H, bd),

Methyl 2(S)-butylsulfonylamino-3-aminopropionatehydrochloride (5-6)

A cooled (-20° C.) solution of 0.400 g (0.00118 mol) of 5-5 in 25 ml ofethyl acetate was treated with HCl gas for 15 min. The resultingsolution was then stoppered and allowed to stir at 0° C. for anadditional hour. The solvent and excess HCl were removed in vacuo togive 5-6 as a hygroscopic, yellowish foam.

¹ H NMR (300 MHz, CDCl₃) δ0.94 (3H, t), 1.44 (9H, s), 1.48 (2H, m), 1.80(2H, m), 3.04 (2H, m), 3.53 (2H, bt), 3.80 (3H, s), 4.22 (1H, m), 4.93(1H, m), 5.40 (1H, bd). ##STR31##

Methyl 2(S)-Methylsulfonylamino-3-aminopropionatehydrochloride (5-7)

5-7 was prepared as described above for the butylsulfonylamino analog(5-6) using methanesulfonyl chloride at the appropriate stage.

¹ H NMR (300 MHz, CD₃ OD) δ3.07 (3H, s), 3.13 (1H, m), 3.43 (1H, dd),3.83 (3H, s), 4.96 (1H, m). ##STR32##

Methyl 2(S)-Phenylsulfonylamino-3-aminopropionate hydrochloride (5-8)

5-8 was prepared as described above for 5-6 using phenylsulfonylchlorideat the appropriate stage.

¹ H NMR (300 MHz, D₂ O) δ3.22 (1H, t), 3.45 (3H, S), 3.51 (2H, m), 4.44(1H, m), 7.61-7.80 (3H, m), 7.92 (2H, m).

2(S)-Benzylureido-3-aminopropionic acid methyl ester hydrochloride(5-10) ##STR33##2(S)-Benzylureido-3-(N-t-butyloxycarbonyl)aminopropionic acid methylester (5-9)

A solution of 5-4 (1.29 g, 5.9 mmoles) in THF (35 ml) was treated withbenzylisocyanate (6.5 mmoles) at room temperature. After stirring for 16hours, the solvent was removed and the residue was purified by flashchromatography on silica gel eluting with 5% MeOH/EtOAc to give 5-9.R_(f) 0.7 (silica, 10% MeOH/EtOAc)

¹ H NMR (300 MHz, CD₃ OD) δ1.45 (9H, s), 3.41 (1H, m), 3.53 (1H, m),3.62 (3H, s), 3.70 (1H, s), 4.32 (3H, m), 5.27 (1H, m), 5.45 (1H, m),5.90 (1H, m).

2(S)-Benzylureido-3-aminopropionic acid methyl ester hydrochloride(5-10)

Treatment of 5-9 (1.91 g) with HCl gas in EtOAc as described for 5-5provided pure 5-10. R_(f) 0.66 (silica, 5% MeOH/CHCl₃ /NH₃)

¹ H NMR (300 MHz, CD₃ OD) δ3.25 (1H, dd) 3.45 (1H, dd), 3.8 (3H, S), 4.4(2H, S), 4.6 (1H, dd), 7.4 (5H, m). ##STR34##

2-[2-(4-N-CBz-Piperidinyl)ethyl]benzimidazole-5-carboxylic acid (6-3)

A solution of methyl-3,4-diaminobenzoate (6.23 g, 37.5 mmol) in 200 mltoluene containing 80 ml of anhydrous pyridine was heated at reflux anda solution containing 3-(4-N-Cbz-Piperidinyl)-propionyl-chloride 6-2(2.90 g, 9.35 mmol) in 60 ml of toluene was added dropwise over 30minutes. The resulting mixture was refluxed for 20 hours then cooled andevaporated. The residue was redissolved in 500 ml CH₂ Cl₂, washedsuccessively with 1N HCl (3×50 ml), H₂ O (100 ml), saturated NaHCO₃(1×100 ml) and brine, then dried over Na₂ SO₄ filtered and evaporated.This yellow residue was chromatographed on silica gel using 3:1 ethylacetate/hexane to give the desired ester.

¹ H NMR (CDCl₃) δ8.25 (s, 1H); 7.95 (d, 1H); 7.55 (d, 1H); 7.36 (m, 5H);5.17 (s, 2H); 4.18 (d, 2H); 3.93 (s, 3H); 2.92 (t, 2H); 2.76 (m, 2H);1.79 (m, 2H); 1.68 (d, 2H); 1.50 (m, 1H); 1.13 (m, 2H).

This ester (1.68 g, 4.0 mmol) was dissolved in 15 ml THF and treatedwith LiOH.H₂ O (185 g, 4.4 mmol) in 10 ml H₂ O. The resulting solutionwas stirred at room temperature for 3.5 hours and then the THF wasevaporated at reduced pressure and the aqueous residue acidified with 3NHCl. The resulting oily precipitate was washed twice with H₂ O thendissolved in 200 ml EtOAc containing 50 ml CH₃ OH, dried over Na₂ SO₄,filtered and evaporated to give 6-3.

¹ H NMR (DMSO-d₆) δ8.35 (s, 1H); 7.97 (d, 1H); 7.55 (d, 1H); 7.36 (m,5H); 5.10 (s, 2H); 4.14 (d, 2H); 3.97 (s, 3H); 2.92 (t, 2H); 2.75 (m,2H); 1.80 (m, 2H); 1.67 (d, 2H); 1.50 (m, 1H); 1.12 (m, 2H). ##STR35##

2-[2-(4-N-Cbz-Piperidinyl)ethyl]benzimidazole-5-carbonyl chloride (6-4)

Acid 6-3 (1.5 g, 3.7 mmol) was suspended in 100 ml of THF and 10 μl DMFwas added followed by 25 ml of oxalyl chloride. The resulting clearsolution was refluxed under N₂ for 2.5 hours, then cooled andevaporated. The resulting yellow powder was triturated with hexane,filtered, washed with 50 ml of hexane and dried under vacuum to give6-4.

¹ H NMR (DMSO-d₆) δ8.53 (s, 1H); 7.93 (d, 1H); 7.57 (d, 1H); 7.36 (m,5H); 5.18 (s, 2H); 4.18 (d, 2H); 2.93 (t, 2H); 2.81 (m, 2H); 1.82 (m,2H); 1.68 (d, 2H); 1.50 (m, 1H); 1.13 (m, 2H). ##STR36##

Methyl-2(S)-Toulenesulfonylamino-3-aminopropionate hydrochloride (6-5)

6-5 was prepared as described above for 5-6 using toluene sulfonylchloride at the appropriate stage.

¹ H NMR (300 MHz, DMSO-d₆) δ7.73 (d, 2H), 7.19 (d, 2H), 6.13 (d, 1H);4.53 (m, 1H); 3.73 (s, 3H); 2.76 (m, 2H); 2.26 (s, 3H). ##STR37##

2-[2-(4-N-Cbz-Piperidinyl)ethyl]benzimidazole-5-carbonyl-[2(S)-p-toluenesulfonylamino]-β-alaninemethyl ester (6-6)

The acid chloride (329 mg, 0.78 mmol) was dissolved in 15 ml of THFalong with 2(S)-toluenesulfonamino-β-alanine methyl ester hydrochloride(6-5) (238 mg, 0.78 mmol). N-methyl morpholine (215 μl, 1.94 mmol) wasadded and the resulting solution was stirred under N₂ for 3.5 h afterwhich the solvent was removed at reduced pressure. The residue wasredissolved in 100 ml CH₂ Cl₂ and washed with 10% KHSO₄ (50 ml) then H₂O (50 ml), dried over Na₂ SO₄ and concentrated. This crude material waspurified by flash chromatography on silica using 5% CH₃ OH/EtOAc aseluent to give pure 6-6.

¹ H NMR (CDCl₃) δ8.15 (br s, 1H); 8.06 (s, 1H); 7.75 (d, 2H); 7.62 (d,1H); 7.45 (d, 1H); 7.36 (m, 6H); 7.18 (d, 2H); 5.10 (s, 2H); 4.18(overlapping m, 3H); 3.82 (m, 2H); 3,64 (s, 3H); 3.01 (t, 2H); 2.76 (m,2H); 2.28 (s, 3H); 1.79 (m, 2H); 1.68 (d, 2H); 1.50 (m, 1H); 1.13 (m,2H). ##STR38##

2-[2-(4-Piperidinyl)ethyl]benzimidazole-5-carbonyl[2(S)-p-toluenesulfonylamino]-β-alanine (6-7)

Ester 6-6 (180 mg, 0.273 mmol) was dissolved in 20 ml 50% aqueous THFand treated with LiOH.H₂ O (12.56 mg, 0.30 mmol) at room temperature for2.5 h. Then the organic solvent was evaporated at reduced pressure andthe aqueous residue was acidified with 1N HCl and extracted with ethylacetate (2×50 ml). The combined organic phases were dried (Na₂ SO₄),filtered and evaporated to give the desired acid.

¹ H NMR (CD₃ OD) δ8.13 (s, 1H); 7.85 (d, 1H); 7.72 (d, 1H); 7.62 (d,2H); 7.32 (m, 5H); 7.18 (d, 2H); 5.14 (s, 2H); 4.21 (overlapping m, 3H);3.82 (m, 1H); 3.62 (m, 1H); 3.13 (t, 2H); 2.82 (m, 2H); 2.28 (s, 3H);1.79 (m, 2H); 1.71 (d, 2H); 1.55 (m, 1H); 1.13 (m, 2H).

This acid (167 mg, .0.258 mmol) was dissolved in 10 ml of absoluteethanol, treated with 20 mg 10% Pd on C, and the mixture was stirredunder a H₂ filled balloon for 16 h. Next, the catalyst was removed byfiltration through Celite and the filtrate evaporated to give pure 6-7,mp 180°-185° (dec.).

¹ H NMR (DMSO-d₆) δ8.15 (br s, 1H); 8.06 (s, 1H); 7.75 (d, 2H); 7.62 (d,1H); 7.45 (d, 1H); 7.18 (d, 2H); 4.18 (overlapping m, 3H); 3.82 (m, 2H);3.64 (s, 3H); 3.01 (t, 2H); 2.76 (m, 2H); 2.28 (s, 3H); 1.79 (m, 2H);1.68 (d, 2H); 1.50 (m, 1H); 1.13 (m, 2H) ##STR39##

2-[2-(4-N-Cbz-Piperidinyl)ethyl]benzimidazole-5-carbonyl-[2(S)-butylsulfonylamino]-β-alanine(6-8)

Treatment of 6-4 with 5-6 as described for 6-6 provided the desiredester which was hydrolyzed with LiOH.H₂ O, as described for 6-7, to give6-8.

¹ H NMR (CD₃ OD) δ8.08 (s, 1H); 7.75 (d, 1H); 7.53 (d, 1H); 7.36 (m,6H); 5.10 (s, 2H); 4.20-4.09 (overlapping multiplets, 5H); 3.82 (dd,1H); 3.62 (dd, 1H); 3.06 (t, 2H); 2.96 (t, 2H); 2.78 (m, 2H); 1.821.62(overlapping multiplets, 6H); 1.50 (m, 1H); 1.38 (m, 2H); 1.13 (m, 2H);0.85 (t, 3H). ##STR40##

2-[2-(4-Piperidinyl)ethyl]benzimidazole-5-carbonyl-[2(S)-butylsulfonylamino]-β-alanine(6-9)

6-8 (153 mg, 0.256 mmol) was dissolved in 10 ml of absolute ethanoltreated with 20 mg 10% Pd on C and mixture stirred under a H₂ filledballoon for 16.5 h. Next, the catalyst was removed by filtration throughCelite and the filtrate evaporated giving a colorless glass which wasvacuum dried over P₂ O₅ at 50° C. to give pure 6-9, mp 180°-185° .

¹ H NMR (CD₃ OD) δ8.12 (s, 1H); 7.73 (d, 1H); 7.52 (d, 1H); 4.18-4.09(overlapping multiplets, 3H); 3.81 (dd, 1H); 358 (dd, 1H); 3.32 (d, 2H);3.03 (t, 2H); 2.95 (t, 2H); 2.78 (m, 2H); 1.82-1.60 (overlappingmultiplets, 6H); 1.48 (m, 1H); 1.38 (m, 2H); 1.13 (m, 2H); 0.85 (t, 3H).##STR41##

3-(4-N-Cbz-Piperidinyl)propanol (6-11)

Commercially available 4-pyridinepropanol (6-10) (38 g, 277 mmol) wasdissolved in 100 ml EtOH/HOAc/H₂ O (4:1:1) and treated with 2.0 g 10%Pd/C. This mixture was hydrogenated on a Parr reactor for 24 h at 55psi. The catalyst was removed by filtration and the filtrate evaporatedto give 3-(4-piperidinyl)propyl acetate.

¹ H NMR (CDCl₃) δ3.65 (t, 2H); 3.52 (d, 2H); 2.81 (t, 2H); 1.75 (d, 2H);1.72 (m, 2H); 1.42 (m, 1H); 1.15 (m, 2H); 1.08 (m, 2H).

A mixture containing this acetate (21.5 g, 107 mmol), NaHCO₃ (17.56 g,208 mmol), 100 ml H₂ O, and 50 ml CH₂ Cl₂ was vigorously stirred in a500 ml flask. To this mixture benzyl chloroformate (16.76 ml, 117 mmol)in 50 ml of CH₂ Cl₂ was added dropwise over a period of 1 h. Theresulting mixture was stirred rapidly for 18 h then the organic phasewas removed and the aqueous phase extracted with CH₂ Cl₂ (2×50 ml). Thecombined organic extracts were dried over Na₂ SO₄, filtered,concentrated, and purified by chromatography on silica (1:1 hexane/ethylacetate) to give 6-11 as a colorless oil.

¹ H NMR (CDCl₃) δ7.34 (m, 5H); 5.12 (s 2H); 4.09 (d, 2H); 3.65 (t, 2H);2.81 (t, 2H); 1.84 (d, 2H); 1.72 (m, 2H); 1.42 (m, 1H); 1.21 (m, 2H);1.08 (m, 2H). ##STR42##

3-(4-N-Cbz-Piperidinyl)propionic acid (6-12)

6-11 (21.0 g, 73.0 mmol) was dissolved in 50 ml acetone and cooled to 0°C. in an ice bath. Next, a solution of 2.67 M Jones reagent (41 ml,109.5 mmol) was added dropwise over 1h and the mixture stirred for anadditional 1 h after the addition was completed. The excess oxidant wasconsumed by adding 10 ml of isopropanol and the insoluble precipitatedissolved by the addition of 150 ml of H₂ O. The acetone was evaporatedat reduced pressure and the aqueous residue extracted with Et₂ O (3×100ml). The combined Et₂ O layers were extracted with sat. NaHCO₃ (2×50ml), the basic extracts acidified with conc. HCl and extracted with CH₂Cl₂ (2×60 ml). The organic extracts were dried (Na₂ SO₄) and evaporatedyielding 6-12 as a colorless viscous oil.

¹ H NMR (CDCl₃) δ7.34 (m, 5H); 5.12 (s, 2H); 4.09 (d, 2H); 2.81 (t, 2H);2.42 (t, 2H); 1.84 (d, 2H); 1.72 (t, 2H); 1.42 (m, 1H); 1.08 (m, 2H).##STR43##

3-(4-N-Cbz-Piperidinyl)carbonyl chloride (6-2)

6-12 (3.0 g, 10.2 mmol) in 10 ml CH₂ Cl₂ was treated with oxalylchloride (1.33 ml, 15.3 mmol) the resulting mixture was stirred at roomtemperature for 1 h then evaporated at reduced pressure and placed on ahigh vacuum line for 18 h giving 6.72 as a pale yellow oil. ¹ H NMR(CDCl₃) δ5 7.35 (m, 5H); 5.12 (s, 2H); 4.18 (d, 2H); 2.93 (t, 2H) 2.75(t, 2H); 1.75-1.69 (m, 4H); 1.43 (m, 1H); 1.08 (m, 2H). ##STR44##

5-Hydroxy-2-indolecarboxylic acid methyl ester (7-2)

5-Hydroxyindole-2-carboxylic acid (Aldrich) (3.54 g, 0.02 mol) intoluene (100 ml)/methanol (25 ml) was treated with TMSCHN₂ (0.022 mol)and this solution was stirred at room temperature for 16 hours. Thesolvent was removed and the residue purified by flash chromatography onsilica gel eluting with CHCl₃ (95)/MeOH(S) to give pure 7-2, R_(f) 0.3,silica, CHCl₃ (95)/MeOH(5).

¹ H NMR (300 MH₃, CDCl₃) δ3.94 (3H, S), 4.79 (1H, S), 6.94 (1H, dd),7.09 (2H, m), 7.28 (1H, m), 8.82 (1H, b). ##STR45##

5-[2-(4-N-BOC-Piperidinylethyl)oxy]-2-indolecarboxylicacid methyl ester(7-4)

A solution of 7-2 (0.96 g, 5 mmol) in THF (15 ml) was treated with PPh₃(1.48 g, 5.5 mmol) and after stirring for 10 minutes, diethylazodicarboxyate (DEAD) (0.96 g, 5.5 mmol) in THF (10 ml) was addeddropwise over 1 hour. After stirring at room temperature for 16 hours,the solvent was removed and the residue was taken up in EtOAc, washedwith H₂ O, saturated NaHCO₃, brine, 10% KHSO₄, brine and dried (Na₂SO₄). The solvent was removed and the residue purified by flashchromatography on silica gel eluting with hexane(4)/EtOAc(1) to givepure 7-4.

¹ H NMR (300 MH₃, CDCl₃) δ1.20 (2H, m), 1.45 (9H, s), 1.59 (1H, s), 1.77(4H, m), 2.71 (2H, bt), 3.92 (3H, s), 4.06 (3H, m), 6.98 (1H, dd), 7.07(1H, m), 7.12 (1H, m), 7.31 (1H, d). ##STR46##

5-[2-(4-N-BOC-Piperidinylethyl)oxy]-2-indolecarbonyl-2(S)-phenyl-sulfonylamino-β-alanine(7-5)

7-4 (0.77 g, 1.9 mmol) was treated with LiOH.H₂ O (0.24 g, 5.7 mmol) asdescribed for 4-1 to give the desired acid. R_(f) 0.5, silica, CHCl₃(95)/MeOH(5).

This acid (0.226 g, 0.58 mmol) was dissolved in DMF and a roomtemperature was treated successively with 5-8 (0.17 g, 5.8 mmol), HOBT(0.086 g, 0.64 mmol), NMM (0.176 g, 1.74 mmol), and EDC (0.13 g, 0.68mmol). After stirring for 24 hours, the solvent was removed and theresidue was taken up in H₂ O (50 ml)/EtOAc(100 ml) and this organicphase was washed with 10% KHSO₄, brine, saturated NaHCO₃, brine anddried (Na₂ SO₄). The solvent was removed and the residue purified byflash chromatography on silica gel eluting with CHCl₃ (95)/MeOH(5) togive pure 7-5.

¹ H NMR (300 MH₃, CD₃ OD) δ1.13 (2H, m), 1.45 (9H, s), 1.73 (4H, m),2.77 (2H, bt), 3.49 (3H, s), 3.57 (1H, m), 3.68 (1H, m), 4.03 (3H, m),4.22 (1H, m), 6.89 (2H, m), 7.04 (1H, m), 7.30-7.43 (4H, m), 7.80 (2H,m). ##STR47##

5-[2-(4-Piperidinylethyl)oxy]-2-indolecarbonyl-2(S)-phenylsulfonyl0amino-.beta.-alanine(7-6)

7-5 (0.33 g, 0.53 mmol) was treated with LiOH.H₂ O (0.066 g, 1.57 mmol)as described for 4-1 to provide the desired acid. R_(f) 0.1, silicaCHCl₃ (95)/CH₃ OH(5)/HOAc(1).

This acid was dissolved in EtOAc, cooled to -25° and treated with HClgas as described for 4-3 to give pure 7-6.

¹ H NMR (300 MH₃, CD₃ OD) δ1.48 (2H, m), 1.80 (2H, m), 1.90-2.08 (3H,m), 3.00 (2H, dt), 3.39 (2H, d), 3.54 (1H, m), 3.73 (1H, dd), 4.08 (2H,m), 4.19 (1H, m), 6.88 (2H, m), 7.09 (1H, m), 7.36 (4H, m), 7.82 (2H,m). ##STR48##

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6-N-[3-(Methyl-2(S)-benzyureidopropionate]carboxamide(8-1)

A solution of 3-3 (0.234 g, 0.0006 mol.), 2-15 (0.173 g, 0.0006 mol.)and HOBT (0.089 g, 0.00066 mol) in DMF (20 ml) was treated with NMM(0.182 g, 0.0018 mol) and EDC (0.144 g, 0.00075 mol) as described for4-1 to give 8-1 Rf 0.46, silica, CHCl₃ (95)/MeOH (S).

¹ H NMR (300 MHZ, CDCl₃) δ1.07-1.23 (2H, m), 1.47 (9H, s), 1.60-1.80(4H, m), 2.57-2.75 (2H, bt), 2.85-3.0 (2H, t), 3.71 (3H, s), 3.73-3.90(2H, bm), 4.00-4.18 (2H, bd), 4.29 (2H, s), 4.67-4.80 (1H, t), 5.40-6.50(2H, vb), 7.00 (1H, s), 7.10-7.23 (5H, bs) 7.47-7.72 (3H, m), 8.20 (1H,s). ##STR49##

2-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-benzylureidopropionicacid)]carboxamide (8-2)

8-1 (0.209 g, 0.000326 mole) was treated with LiOH.H₂ O as described for2-5 to give 8-2.

¹ H NMR (300 MHZ, CDCl₃) δ1.04-1.25 (2H, m), 1.45-1.60 (1H, m), 1.45(9H, s), 1.60-1.82 (4H, m), 2.56-2.76 (2H, bt), 2.80-3.00 (2H, t),3.68-3.95 (2H, m), 3.97-4.32 (4H, m), 4.46-4.60 (1H, b), 6.00-6.40 (1H,b), 6.60-6.85 (1H, b), 6.94 (1H, s), 7.00-7.23 (5H, m), 7.50-7.67 (2H,dd) 7.70-7.85 (1H, b), 8.14 (1H, s). ##STR50##

2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-benzylureidopropionicacid]carboxamide (8-3)

8-2 was suspended in EtOAc and treated with HCl (g) as described for 3-5to give 8-3 Rf 0.52, silica, EtOH(10)/--H₂ O (1)/--NH₄ OH (1).

¹ H NMR (300 MHz, CD₃ OD) δ1.45-1.55 (2H, m) 1.62-1.94 (3H, m),1.96-2.12 (2H, 6d), 2.88-3.12 (4H, m), 3.30-3.45 (2H, m), 3.70-3.85 (2H,t), 4.20-4.37 (2H, q), 4.58-4.67 (1H, dd), 7.02-7.25 (6H, m), 7.72 (2H,s), 8.25 (1H, s).

In addition to those compounds specifically exemplified above,additional compounds of the present invention are set forth in tabularform below. These compounds are synthesized by use of the syntheticroutes and methods described in the above Schemes and Examples andvariations thereof well known to those of ordinary skill in the art, andnot requiring undue experimentation. All variables listed in the Tablesbelow are with reference to the following generic structure:

    __________________________________________________________________________     ##STR51##                                                                    X        Y          D   E   R.sup.12                                                                              A      B                                  __________________________________________________________________________    CH.sub.3 NH                                                                            (CH.sub.2).sub.5 SO.sub.2                                                                O   N   CH.sub.3                                                                               ##STR52##                                                                            ##STR53##                          ##STR54##                                                                             (CH.sub.2).sub.3 O                                                                       S   N   F                                                                                      ##STR55##                                                                            ##STR56##                          ##STR57##                                                                             (CH.sub.2).sub.2 OCH.sub.2                                                               CH  O   CH.sub.2 CF.sub.3                                                                     CHCH                                                                                  ##STR58##                          ##STR59##                                                                             CH.sub.2 SO.sub.2 (CH.sub.2).sub.2                                                       CH  N   CH.sub.2 OCH.sub.3                                                                    CC                                                                                    ##STR60##                          ##STR61##                                                                              ##STR62## O   CH  CH.sub.2 CO.sub.2 Me                                                                  CH.sub.2 SO.sub.2 NH                                                                  ##STR63##                          ##STR64##                                                                              ##STR65## S   CH  H                                                                                      ##STR66##                                                                            ##STR67##                          ##STR68##                                                                              ##STR69## O   N   OC.sub.2 H.sub.5                                                                       ##STR70##                                                                            ##STR71##                          ##STR72##                                                                             CH.sub.2 S NH  N   H       NHSO.sub.2                                                                            ##STR73##                          ##STR74##                                                                             CHCH       O   CH  Ph      CH.sub.2                                                                              ##STR75##                         H.sub.2 N                                                                              (CH.sub.2).sub.6                                                                         CH  N   OCH.sub.3                                                                             CCH.sub.2                                                                             ##STR76##                          ##STR77##                                                                             OCH.sub.2  NH  N   H                                                                                      ##STR78##                                                                            ##STR79##                          ##STR80##                                                                             CH.sub.2   O   N   CH.sub.3                                                                               ##STR81##                                                                            ##STR82##                          ##STR83##                                                                              ##STR84## S   CH  H       SO.sub.2 CH.sub.2                                                                     ##STR85##                          ##STR86##                                                                              ##STR87## O   CH  Cl      CC                                                                                    ##STR88##                          ##STR89##                                                                             CH.sub.2 CH.sub.2 CH.sub.2                                                               CH  N   H                                                                                      ##STR90##                                                                            ##STR91##                         __________________________________________________________________________

What is claimed is:
 1. A compound of the formula ##STR92## wherein m is0-6;D is O,S, or N; E is C or N; A is(CH₂)_(n), wherein n is 0-6, or##STR93## B is ##STR94## R¹⁰ is carboxyC₀₋₆ alkyl,benzyloxycarbonylamino, C₁₋₈ alkylsulfonylamino, or phenylC₀₋₈alkylaminocarbonylaminoC₀₋₆ alkyl; and R¹¹ is hydroxy or alkoxy.
 2. Acompound of claim 1 having the formula ##STR95## wherein m is 0-6D is O;E is C; A is(OH₂)_(n), wherein n is 0-6, or ##STR96## B is ##STR97## R¹⁰is C₁₋₈ alkylsulfonylamino; and R¹¹ is hydroxy or alkoxy.
 3. A compoundof claim 1 selected from the group consisting of2-(Butylsulfonylamino)-3-{5-[2'-(4-piperidin-4-yl-propyl)benzofuranyl]}propanoic acid;2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-N-carbobenzyloxyaminopropionicacid)-carboxamide;2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-N-butylsulfonylaminopropionicacid)-carboxamide;2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[3-(2(S)-N-Methylsulfonylaminopropionicacid)]-carboxamide;2-[2-(4-Piperidinyl)ethyl]benzimidazole-5-carbonyl-[2(S)-butylsulfonylamino]-b-alanine;and2-[2-(Piperidin-4-yl)ethyl]benzothiophene-6-N-[N3-(2-(S)-benzylureido)propionicacid]carboxamide.
 4. A composition for inhibiting the binding offibrinogen to blood platelets in a mammal, comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 5. A method forinhibiting the binding of fibrinogen to blood platelets in a mammal,comprising administering to the mammal a composition of claim 4.